BP1 and Nuclear Hormone Signaling in Breast Cancer

描述（由申请人提供）：这是一项“面向患者的研究中期研究者奖：PA-00-005”，题为“造血障碍的治疗策略”。血细胞的形成代表了干细胞、构成基质微环境的细胞和生长调节蛋白之间复杂的相互作用，这些蛋白以可溶性和局部形式存在。这些相互作用产生了数量庞大、种类繁多的细胞，这些细胞在身体的不同部位发挥作用，运输氧气，抵御感染因子，并为凝血提供刺激。损害血细胞发育过程的异常，如骨髓发育不良和急性髓性白血病（AML）；以及癌症，可导致危及生命的疾病，以及谱系特异性骨髓抑制或全血细胞减少症，导致显著的发病率和死亡率。本提案的重点是发展、开展和指导基于科学的、假设驱动的试点临床研究，旨在利用这些特定疾病的固有生物学特征。三个不同的中心假设是候选人目前（目前资助）和新的（由K24支持）临床研究工作的基础：1)干扰或逆转录抑制药物的治疗应用将分别在AML和MDS中具有临床效用；2)抑制自分泌和微环境呈现的生长因子，它们有助于延迟程序性细胞死亡，这是慢性淋巴细胞白血病（CLL）等疾病的特征，代表了一种潜在实用的新型治疗方法；3)红细胞生成细胞因子抑制与癌症贫血有关；克服细胞因子抑制的策略应该增加癌症患者的红细胞生成，并进一步减少该人群贫血的临床问题。这一应用的一个重要部分是对选择学术临床研究作为职业道路的关键初级教员和血液学/肿瘤学研究员的积极指导。该指导计划包括：1)参加与NIH资助的临床研究培训计划（K30）相关的特定课程，候选人担任首席研究员，以及临床研究行为的IRB课程；2)直接监督，包括每周的会议，以便：(a)协议和IND开发；(b)应计、数据和监管审查；(c)手稿和陈述准备。

DESCRIPTION (provided by applicant): This is a "Midcareer Investigator Award in Patient-Oriented Research: PA-00-005" entitled Therapeutic Strategies in Disorders of Hematopoiesis. The formation of blood cells represents a complex interaction between stem cells, ceils making up the stromal microenvironment and growth regulatory proteins, which are presented in soluble and localized forms. These interactions give rise to an enormous number and diversity of cells that function in widely separated parts of the body to transport oxygen, defend against infectious agents and provide stimulus for clotting. Abnormalities that impair the process of blood cell development, such as Myelodysplasia and Acute Myelogenous Leukemia (AML); as well as Cancer, can lead to life threatening illness as welt as lineage specific myelosuppression or pancytopenia resulting in significant morbidity and mortality. This proposal focuses on the development, conduct and mentoring of scientifically based, hypothesis-driven pilot clinical investigations, designed to exploit inherent biological features of these specific diseases. Three distinct central hypotheses underlie the Candidate's present (currently funded) and new (to be supported by K24) clinical research efforts: 1) the therapeutic application of agents that interfere or reverse transcriptional repression will be of clinical utility in AML and MDS respectively; 2) inhibition of autocrine and microenvironmentally presented growth factors, which contribute to delays in programmed cell death, characteristic of disorders such as chronic lymphocytic leukemia (CLL), represents a novel therapeutic approach of potential utility; and 3) cytokines inhibitory for erythropoiesis contribute to anemia of cancer; strategies to overcome cytokine inhibition should augment red blood cell production in cancer patients and further reduce the clinical problem of anemia in this population. An important part of this application concerns the active mentorship of key junior faculty and hematology/oncology fellows who have chosen to pursue academic clinical research as a career path. This mentorship program consists of: 1) participation in specific curriculum in conjunction with the NIH funded Clinical Research Training Program (K30), for which the candidate serves as the Principal investigator, and IRB course on conduct in Clinical Research; 2) direct oversight, including weekly meetings for: (a) protocol and IND development; (b) accrual, data and regulatory review; (c) manuscript and presentation preparation.